Preventive or therapeutic medicines for diabetes containing fused-heterocyclic compounds or their salts

ABSTRACT

The present invention provides a preventive or therapeutic medicine for diabetes containing as an active ingredient a fused-heterocyclic compound of the formula (I′) or its salt:  
                 
 
     [wherein G is CN, NO 2 , CO 2 R 4 , CHO, SO 2 NR a R b  or CONR a R b ; R 1  is a halogen atom, a —O—R 5  group or a —S—R 5  group; R 2  is a halogen atom, a O—R 5  group (wherein R 5  is as defined above) or an amino group which may be substituted; and each of R 8  and R 10  which are independent of each other, is a hydrogen atom, a halogen atom or an alkyl group].

TECHNICAL FIELD

[0001] The present invention relates to preventive or therapeuticmedicines for diabetes, which contain specific fused-heterocycliccompounds or their salts as active ingredients. Further, some offused-heterocyclic compounds or their salts as described hereinafter arenovel substances. The preventive or therapeutic medicines for diabetesof the present invention have a stimulating effect on glucose uptake anda hypoglycemic effect, and they are useful as preventive or therapeuticmedicines for diabetes; impaired glucose tolerance; various diabeticcomplications such as hyperlipidemia, vascular diseases, retinopathy,nephropathy, neuropathy and hypertension; and obesity.

BACKGROUND ART

[0002] As general antidiabetic agents having a hypoglycemic effect,insulin preparations and oral hypoglycemic agents are mainly utilized.The oral hypoglycemic agents may, for example, be islet-activatingagents represented by sulfonylurea agents, liver gluconeogenesisinhibitors represented by biguanides and insulin sensitizers representedby thiazolidine derivatives. However, these therapeutic medicines arenot effectively affect on many patients, and it is not easy to controlthe blood glucose level only by these therapeutic medicines, and variousdiabetic complications are caused in fact. Among peripheral organs inthe body, a muscle is the most important tissue which plays a role ofglucose metabolism at the time of hyperglycemia, and a decrease inglucose uptake activity of skeletal muscle cells is considered to be oneof great factors causing hyperglycemia to diabetic patients. Therapeuticmedicines for diabetes which directly accelerate glucose uptake activityin skeletal muscles as a principal action without depending on insulinare hypoglycemic agents of new types, and therapeutic medicines asdisclosed in JP-A-6-345647 and JP-A-8-12579 have been proposed, but havenot been used practically yet. These patent applications disclose thatit takes so long time of 24 hours to apply a compound under test toskeletal muscle cells, and do not disclose the effect in a case ofapplication for a level of 1 hour. The present inventors have found thata stimulating effect on glucose uptake is obtained by applying compoundsof the formula (I) as described hereinafter having structures totallydifferent from those in the above patent applications to skeletal musclecells for a short time. Further, they have also confirmed that thecompounds of the formula (I) as described hereinafter show ahypoglycemic effect or an effect of improving impaired glucosetolerance, several hours after administration of the compounds todiabetic KK-Ay mice and the like.

[0003] As compounds having chemical structures analogous to those of thecompounds of the formula (I) as described hereinafter, compounds asdisclosed in WO97/35550, WO99/60858 and WO00/44754 may be mentioned.However, these patent applications fail to disclose the effect asstimulators of glucose uptake in skeletal muscle cells.

DISCLOSURE OF THE INVENTION

[0004] The present inventors have found that when a specificfused-heterocyclic compound or its salt is applied to skeletal musclecells for a short time, a stimulating effect on glucose uptake isobtained, and the present invention has been accomplished on the basisof this discovery.

[0005] The present inventors have conducted extensive studies to findmore excellent antidiabetic agents and as a results, have accomplishedthe present invention. Namely, the present invention relates to apreventive or therapeutic medicine for diabetes containing as an activeingredient a fused-heterocyclic compound of the formula (I) or its salt:

[0006] [wherein A is a nitrogen atom or C-G {wherein G is CN, NO₂, SO₂R³(wherein R³ is an alkyl group which may be substituted, an alkenyl groupwhich may be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted or aheterocyclic group which may be substituted), CO₂R⁴ (wherein R⁴ is ahydrogen atom, an alkyl group which may be substituted, an alkenyl groupwhich may be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted or aheterocyclic group which may be substituted), CHO, SO₂NR^(a)R^(b)(wherein each of R^(a) and R^(b) which are independent of each other, isa hydrogen atom, a hydroxyl group, an alkoxy group, an alkyl group whichmay be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted or a heterocyclic group which may besubstituted, or R^(a) and R^(b) together form a ring) or CONR^(a)R^(b)(wherein R^(a) and R^(b) are as defined above)};

[0007] each of R¹ and R² which are independent of each other, is ahydrogen atom, a halogen atom, an alkyl group which may be substituted,an alkenyl group which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substituted,a heterocyclic group which may be substituted, a —B¹—R⁵ group (whereinB¹ is CO, COO, O, OCO, OSO₂, S, SO or SO₂, and R⁵ is a hydrogen atom, analkyl group which may be substituted, an alkenyl group which may besubstituted, an alkynyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted, an aryl group which may be substituted or a heterocyclicgroup which may be substituted), an amino group which may be substitutedor —N═CR⁶R⁷ (wherein each of R⁶ and R⁷ which are independent of eachother, is a hydrogen atom, an alkyl group which may be substituted, analkenyl group which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substitutedor a heterocyclic group which may be substituted);

[0008] each of Y and Z which are independent of each other, is anitrogen atom or C—R⁸ (wherein R⁸ is a hydrogen atom, a halogen atom, analkyl group which may be substituted, an alkenyl group which may besubstituted, an alkynyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted, an aryl group which may be substituted, a heterocyclicgroup which may be substituted, a —B²—R⁹ group (wherein B² is CO, COO,O, OCO, OSO₂, S, SO or SO₂, and R⁹ is a hydrogen atom, an alkyl groupwhich may be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted or a heterocyclic group which may besubstituted), an amino group which may be substituted, a cyano group ora nitro group), provided that when Y and Z are simultaneously C—R⁸, thetwo R⁸'s may be the same or different;

[0009] X is a nitrogen atom or C—R¹⁰ (wherein R¹⁰ is a hydrogen atom, ahalogen atom, an alkyl group which may be substituted, an alkenyl groupwhich may be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, a —B²—R⁹ group (wherein B² and R⁹ are as definedabove), an amino group which may be substituted, a cyano group or anitro group); and

[0010] in a case where Y is C—R⁸, and X is C—R¹⁰ or Z is C—R⁸, R⁸ andR¹⁰ or two R⁸'s together may form a ring containing or not containing ahetero atom].

[0011] The salt of the fused-heterocyclic compound of the above formula(I) may be any pharmaceutically acceptable salt, and it may, forexample, be a mineral acid salt such as a hydrochloride, a sulfate or anitrate; an organic acid salt such as a p-toluenesulfonate, a propanesulfonate or a methane sulfonate; an alkali metal salt such as apotassium salt or a sodium salt; an alkaline earth metal salt such as acalcium salt; or an organic amine salt such as a triethanol amine saltor a tris(hydroxymethyl) aminomethane salt. Some of these salts havecrystal water.

[0012] The alkyl moiety of the alkyl group which may be substitutedrepresented by each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^(a)and R^(b) in the formula (I) may be usually one having a carbon numberof from 1 to 18, and it may, for example, be a methyl group, an ethylgroup, a propyl group, a butyl group, a pentyl group, a hexyl group, anoctyl group, a nonyl group, a decyl group or a nonadecyl group, and theyinclude linear or branched aliphatic structural isomers.

[0013] The alkenyl moiety of the alkenyl group which may be substitutedor the alkynyl moiety of the alkynyl group which may be substituted,represented by each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^(a)and R^(b) in the formula (I), may be usually one having a carbon numberof from 2 to 18, and they include linear or branched aliphaticstructural isomers.

[0014] The cycloalkyl moiety of the cycloalkyl group which may besubstituted or the cycloalkenyl moiety of the cycloalkenyl group whichmay be substituted, represented by each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R^(a) and R^(b) in the formula (I), may be usually onehaving a carbon number of from 3 to 10, and it may, for example, be amonocyclic group such as a cyclopropyl group, a cyclobutyl group, acyclopentyl group, a cyclohexyl group, a cyclopentenyl group or acyclohexenyl group, a fused-polycyclic group or a crosslinked polycyclicgroup.

[0015] The aryl moiety of the aryl group which may be substitutedrepresented by each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R^(a) andR^(b) in the formula (I) may be a fused-polycyclic group such as anaphthyl group, as well as a phenyl group.

[0016] The heterocyclic moiety of the heterocyclic group which may besubstituted represented by each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,R^(a) and R^(b) in the formula (I), may, for example, be a monocyclicheterocyclic group such as a pyrrolyl group, a pyrrolinyl group, apyrrolidinyl group, a furanyl group, a dihydrofuranyl group, atetrahydrofuranyl group, a thienyl group, a dihydrothienyl group, atetrahydrothienyl group, a pyrazolyl group, a pyrazolinyl group, apyrazolidinyl group, an imidazolyl group, an imidazolinyl group, animidazolidinyl group, an oxazolyl group, an oxazolinyl group, anoxazolidinyl group, an isoxazolyl group, an isoxazolinyl group, anisoxazolidinyl group, a thiazolyl group, a thiazolinyl group, athiazolidinyl group, an isothiazolyl group, an isothiazolinyl group, anisothiazolidinyl group, an oxadiazolyl group, an oxadiazolinyl group, anoxadiazolidinyl group, a thiadiazolyl group, a thiadiazolinyl group, athiadiazolidinyl group, a triazolyl group, a triazolinyl group, atriazolidinyl group, a tetrazolyl group, a tetrazolinyl group, atetrazolidinyl group, a dioxolyl group, a dioxolanyl group, a dithiolylgroup, a dithiolanyl group, a pyridyl group, a dihydropyridyl group, atetrahydropyridyl group, a piperidinyl group, a pyrimidyl group, adihydropyrimidyl group, a tetrahydropyrimidyl group, ahexahydropyrimidyl group, a pyridazinyl group, a dihydropyridazinylgroup, a tetrahydropyridazinyl group, a hexahydropyridazinyl group, apyrazinyl group, a dihydropyrazinyl group, a tertahydropyrazinyl group,a piperazinyl group, a pyranyl group, a dihydropyranyl group, atetrahydropyranyl group, a dioxinyl group, a dioxenyl group, a dioxanylgroup, a dithianyl group or a morpholinyl group; a fused-polycyclicheterocyclic group such as a thienothienyl group, adihydrocyclopentathienyl group, an indolyl group, a tetrahydroindolylgroup, an isoindolyl group, a tetrahydroisoindolyl group, a benzothienylgroup, a tetrahydrobenzothienyl group, a benzofuranyl group, atetrahydrobenzofuranyl group, a benzoxazolyl group, atetrahydrobenzoxazolyl group, a benzoisoxazolyl group, atetrahydrobenzoisoxazolyl group, a benzothiazolyl group, atetrahydrobenzothiazolyl group, a benzoisothiazolyl group, atetrahydrobenzoisothiazolyl group, a benzoimidazolyl group, atetrahydrobenzimidazolyl group, a benzodioxolyl group, a benzodithiolylgroup, a benzodioxanyl group, a benzodithianyl group, a quinolinylgroup, an isoquinolinyl group, a quinazolinyl group, a quinoxalinylgroup, a phthalazinyl group, a naphthylidinyl group or a purinyl group;or a crosslinked polycyclic heterocyclic group such as a quinuclidinylgroup.

[0017] The secondary substituent of each of the alkyl group which may besubstituted, the alkenyl group which may be substituted and the alkynylgroup which may be substituted, represented by each of R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R^(a) and R^(b) in the formula (I), may, forexample, be a halogen atom, a hydroxyl group, a mercapto group, asubstitutable alkoxy group, a substitutable alkylthio group, asubstitutable alkenyloxy group, a substitutable alkenylthio group, asubstitutable alkynyloxy group, a substitutable alkynylthio group, asubstitutable cycloalkyl group, a substitutable cycloalkenyl group, asubstitutable cycloalkoxy group, a substitutable cycloalkylthio group, asubstitutable cycloalkenyloxy group, a substitutable cycloalkenylthiogroup, a substitutable alkoxycarbonyl group, a substitutablealkylcarbonyl group, a substitutable alkylcarbonyloxy group, asubstitutable alkenyloxycarbonyl group, a substitutable alkenylcarbonylgroup, a substitutable alkenylcarbonyloxy group, a substitutablealkynyloxycarbonyl group, a substitutable alkynylcarbonyl group, asubstitutable alkynylcarbonyloxy group, a substitutablecycloalkoxycarbonyl group, a substitutable cycloalkylcarbonyl group, asubstitutable cycloalkylcarbonyloxy group, a substitutablecycloalkenyloxycarbonyl group, a substitutable cycloalkenylcarbonylgroup, a substitutable cycloalkenylcarbonyloxy group, a substitutablearyl group, a substitutable aryloxy group, a substitutable arylthiogroup, a substitutable aryloxycarbonyl group, a substitutablearylcarbonyl group, a substitutable arylcarbonyloxy group, asubstitutable heterocyclic group, a substitutable heterocyclyloxy group,a substitutable heterocyclylthio group, a substitutableheterocyclyloxycarbonyl group, a substitutable heterocyclylcarbonylgroup, a substitutable heterocyclylcarbonyloxy group, a substitutableamino group, a cyano group, a nitro group, a carboxyl group, asubstitutable aminocarbonyl group, a substitutable alkylsulfonyl group,a substitutable alkenylsulfonyl group, a substitutable alkynylsulfonylgroup, a substitutable cycloalkylsulfonyl group, a substitutablecycloalkenylsulfonyl group, a substitutable arylsulfonyl group, asubstitutable heterocyclylsulfonyl group or a substitutableaminosulfonyl group. The number of such substituents may be one or twoor more, and when the number of the substituents is two or more, suchsubstituents may be the same or different.

[0018] The secondary substituent of each of the cycloalkyl group whichmay be substituted, the cycloalkenyl group which may be substituted, thearyl group which may be substituted and the heterocyclic group which maybe substituted, represented by each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R^(a) and R^(b) in the formula (I), may, for example, be ahalogen atom, a hydroxyl group, a mercapto group, a substitutable alkylgroup, a substitutable alkenyl group, a substitutable alkynyl group, asubstitutable alkoxy group, a substitutable alkylthio group, asubstitutable alkenyloxy group, a substitutable alkenylthio group, asubstitutable alkynyloxy group, a substitutable alkynylthio group, asubstitutable cycloalkyl group, a substitutable cycloalkenyl group, asubstitutable cycloalkoxy group, a substitutable cycloalkylthio group, asubstitutable cycloalkenyloxy group, a substitutable cycloalkenylthiogroup, a substitutable alkoxycarbonyl group, a substitutablealkylcarbonyl group, a substitutable alkylcarbonyloxy group, asubstitutable alkenyloxycarbonyl group, a substitutable alkenylcarbonylgroup, a substitutable alkenylcarbonyloxy group, a substitutablealkynyloxycarbonyl group, a substitutable alkynylcarbonyl group, asubstitutable alkynylcarbonyloxy group, a substitutablecycloalkoxycarbonyl group, a substitutable cycloalkylcarbonyl group, asubstitutable cycloalkylcarbonyloxy group, a substitutablecycloalkenyloxycarbonyl group, a substitutable cycloalkenylcarbonylgroup, a substitutable cycloalkenylcarbonyloxy group, a substitutablearyl group, a substitutable aryloxy group, a substitutable arylthiogroup, a substitutable aryloxycarbonyl group, a substitutablearylcarbonyl group, a substitutable arylcarbonyloxy group, asubstitutable heterocyclic group, a substitutable heterocyclyloxy group,a substitutable heterocyclylthio group, a substitutableheterocyclyloxycarbonyl group, a substitutable heterocyclylcarbonylgroup, a substitutable heterocyclylcarbonyloxy group, a substitutableamino group, a cyano group, a nitro group, a carboxyl group, asubstitutable aminocarbonyl group, a substitutable alkylsulfonyl group,a substitutable alkenylsulfonyl group, a substitutable alkynylsulfonylgroup, a substitutable cycloalkylsulfonyl group, a substitutablecycloalkenylsulfonyl group, a substitutable arylsulfonyl group, asubstitutable heterocyclylsulfonyl group or a substitutableaminosulfonyl group. The number of such substituents may be one or twoor more, and when the number of the substituents is two or more, suchsubstituents may be the same or different.

[0019] The secondary substituent of the amino group which may besubstituted represented by each of R¹, R², R⁸ and R¹⁰ in the formula(I), may, for example, be a hydroxyl group, a substitutable alkyl group,a substitutable alkenyl group, a substitutable alkynyl group, asubstitutable alkoxy group, a substitutable alkenyloxy group, asubstitutable alkynyloxy group, a substitutable cycloalkyl group, asubstitutable cycloalkenyl group, a substitutable cycloalkoxy group, asubstitutable cycloalkenyloxy group, a substitutable alkoxycarbonylgroup, a substitutable alkylcarbonyl group, a substitutablealkenyloxycarbonyl group, a substitutable alkenylcarbonyl group, asubstitutable alkynyloxycarbonyl group, a substitutable alkynylcarbonylgroup, a substitutable cycloalkoxycarbonyl group, a substitutablecycloalkylcarbonyl group, a substitutable cycloalkenyloxycarbonyl group,a substitutable cycloalkenylcarbonyl group, a substitutable aryl group,a substitutable aryloxy group, a substitutable aryloxycarbonyl group, asubstitutable arylcarbonyl group, a substitutable heterocyclic group, asubstitutable heterocyclyloxy group, a substitutableheterocyclyloxycarbonyl group, a substitutable heterocyclylcarbonylgroup, a substitutable aminocarbonyl group, a substitutablealkylsulfonyl group, a substitutable alkenylsulfonyl group, asubstitutable alkynylsulfonyl group, a substitutable cycloalkylsulfonylgroup, a substitutable cycloalkenylsulfonyl group, a substitutablearylsulfonyl group, a substitutable heterocyclylsulfonyl group or asubstitutable aminosulfonyl group. The number of such secondarysubstituents may be one or two, and when the number is two, they may bethe same or different. Further, the two secondary substituents may forma ring containing or not containing a hetero atom.

[0020] The tertiary substituent of each of substitutable groups amongthe above secondary substituents may, for example, be a halogen atom, ahydroxyl group, a mercapto group, a cyano group, a nitro group, acarboxyl group, an amino group, an alkyl group, an alkenyl group, analkynyl group, a cycloalkyl group, a cycloalkenyl group, an aryl group,a heterocyclic group, an alkoxy group, an alkenyloxy group, analkynyloxy group, a cycloalkyloxy group, a cycloalkenyloxy group, anaryloxy group, a heterocyclyloxy group, an alkylthio group, analkenylthio group, an alkynylthio group, a cycloalkylthio group, acycloalkenylthio group, an arylthio group, a heterocyclylthio group, analkylsulfonyl group, an alkenylsulfonyl group, an alkynylsulfonyl group,a cycloalkylsulfonyl group, a cycloalkenylsulfonyl group, anarylsulfonyl group, a heterocyclylsulfonyl group, an alkylcarbonylgroup, an alkenylcarbonyl group, an alkynylcarbonyl group, acycloalkylcarbonyl group, a cycloalkenylcarbonyl group, an arylcarbonylgroup, a heterocyclylcarbonyl group, an alkyloxycarbonyl group, analkenyloxycarbonyl group, an alkynyloxycarbonyl group, acycloalkyloxycarbonyl group, a cycloalkenyloxycarbonyl group, anaryloxycarbonyl group, a heterocyclyloxycarbonyl group, an aminocarbonylgroup, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, analkenylaminocarbonyl group, an alkynylaminocarbonyl group, acycloalkylaminocarbonyl group, a cycloalkenylaminocarbonyl group, anarylaminocarbonyl group, a heterocyclylaminocarbonyl group, anaminosulfonyl group, an alkylaminosulfonyl group, a dialkylaminosulfonylgroup, an alkenylaminosulfonyl group, an alkynylaminosulfonyl group, acycloalkylaminosulfonyl group, a cycloalkenylaminosulfonyl group, anarylaminosulfonyl group, a heterocyclylaminosulfonyl group, analkylamino group, a dialkylamino group, an alkenylamino group, analkynylamino group, a cycloalkylamino group, a cycloalkenylamino group,an arylamino group, a heterocyclylamino group, an alkylcarbonylaminogroup, an alkenylcarbonylamino group, an alkynylcarbonylamino group, acycloalkylcarbonylamino group, a cycloalkenylcarbonylamino group, anarylcarbonylamino group, a heterocyclylcarbonylamino group, analkylsulfonylamino group, an alkenylsulfonylamino group, analkynylsulfonylamino group, a cycloalkylsulfonylamino group, acycloalkenylsulfonylamino group, an arylsulfonylamino group or aheterocyclylsulfonylamino group. The number of such tertiarysubstituents may be one or two or more, and when the number is two ormore, such substituents may be the same or different. Further, when thesecondary substituent is an amino group substituted with two tertiarysubstituents, such tertiary substituents together may form a ringcontaining or not containing a hetero atom.

[0021] Further, each of the alkyl moiety, the alkenyl moiety, thealkynyl moiety, the cycloalkyl moiety, the cycloalkenyl moiety, the arylmoiety and the heterocyclic moiety of each of such tertiary substituentsmay further be substituted with a quaternary substituent such as ahalogen atom, a hydroxyl group, a mercapto group, a cyano group, a nitrogroup, a carboxyl group, an amino group, an alkyl group, a haloalkylgroup, an alkoxy group, a haloalkoxy group, an alkylthio group, ahaloalkylthio group, an alkoxycarbonyl group, an aminocarbonyl group, analkylaminocarbonyl group, a dialkylaminocarbonyl group, an aminosulfonylgroup, an alkylaminosulfonyl group, a dialkylaminosulfonyl group, analkylamino group, a dialkylamino group, an alkylcarbonylamino group, analkylsulfonylamino group, a cycloalkyl group, an aryl group or aheterocyclic group. The number of such substituents may be one or two ormore, and when the number of the substituents is two or more, suchsubstituents may be the same or different.

[0022] Among the fused-heterocyclic compounds of the above formula (I)and their salts, fused-heterocyclic compounds of the formula (I′) andtheir salts:

[0023] [wherein G is CN, NO₂, CO₂R⁴ (wherein R⁴ is a hydrogen atom, analkyl group which may be substituted, an alkenyl group which may besubstituted, an alkynyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted, an aryl group which may be substituted or a heterocyclicgroup which may be substituted), CHO, SO₂NR^(a)R^(b) (wherein each ofR^(a) and R^(b) which are independent of each other, is a hydrogen atom,a hydroxyl group, an alkoxy group, an alkyl group which may besubstituted, an alkenyl group which may be substituted, an alkynyl groupwhich may be substituted, a cycloalkyl group which may be substituted, acycloalkenyl group which may be substituted, an aryl group which may besubstituted or a heterocyclic group which may be substituted, or R^(a)and R^(b) together form a ring) or CONR^(a)R^(b) (wherein R^(a) andR^(b) are as defined above);

[0024] R¹ is a halogen atom, a —O—R⁵ group (wherein R⁵ is a hydrogenatom, an alkyl group which may be substituted, an alkenyl group whichmay be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted or aheterocyclic group which may be substituted) or a —S—R⁵ group (whereinR⁵ is as defined above);

[0025] R² is a halogen atom, a —O—R⁵ group (wherein R⁵ is as definedabove) or an amino group which may be substituted; and

[0026] each of R⁸ and R¹⁰ which are independent of each other, is ahydrogen atom, a halogen atom or an alkyl group], are novel compounds.

BEST MODE FOR CARRYING OUT THE INVENTION

[0027] Now, some of preferred embodiments of the present invention willbe explained, however, the present invention is by no means restrictedthereto.

[0028] The compounds of the above formula (I) and the compounds of theformula (I′) included therein, are useful as active ingredients forpreventive or therapeutic medicines for diabetes, and are useful as thefollowing agents for example.

[0029] (1) Stimulators of glucose uptake in skeletal muscle cells.

[0030] (2) Hypoglycemic agents.

[0031] (3) Preventive or therapeutic medicines for impaired glucosetolerance.

[0032] (4) Preventive or therapeutic medicines for diabeticcomplications.

[0033] (5) Preventive or therapeutic medicines for at least one diabeticcomplication selected from the group consisting of hyperlipidemia,vascular diseases, retinopathy, nephropathy, neuropathy andhypertension.

[0034] (6) Preventive or therapeutic medicines for obesity.

[0035] Among the compounds of the above formula (I), the followingcompounds are excellent as active ingredients for preventive ortherapeutic medicines for diabetes.

[0036] (1) Compounds wherein A is C-G {wherein G is CN, NO₂, CO₂R⁴(wherein R⁴ is a hydrogen atom, an alkyl group which may be substituted,an alkenyl group which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substitutedor a heterocyclic group which may be substituted), CHO, SO₂NR^(a)R^(b)(wherein each of R^(a) and R^(b) which are independent of each other, isa hydrogen atom, a hydroxyl group, an alkoxy group, an alkyl group whichmay be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted or a heterocyclic group which may besubstituted, or R^(a) and R^(b) together form a ring) or CONR^(a)R^(b)(wherein R^(a) and R^(b) are as defined above)};

[0037] each of Y and Z which are independent of each other, is anitrogen atom or C—R⁸ {wherein R⁸ is a hydrogen atom, a halogen atom, analkyl group which may be substituted, an alkenyl group which may besubstituted, an alkynyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted, an aryl group which may be substituted, a heterocyclicgroup which may be substituted, a —B²—R⁹ group (wherein B² is CO, COO,O, OCO, OSO₂, S, SO or SO₂, and R⁹ is a hydrogen atom, an alkyl groupwhich may be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted or a heterocyclic group which may besubstituted), an amino group which may be substituted, a cyano group ora nitro group}, provided that when Y and Z are simultaneously C—R⁸, thetwo R⁸'s may be the same or different; and

[0038] X is a nitrogen atom or C—R¹⁰ {wherein R¹⁰ is a hydrogen atom, ahalogen atom, an alkyl group which may be substituted, an alkenyl groupwhich may be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, a —B²—R⁹ group (wherein B² and R⁹ are as definedabove), an amino group which may be substituted, a cyano group or anitro group}.

[0039] (2) Compounds wherein each of R¹ and R² which are independent ofeach other, is a halogen atom, an alkyl group which may be substituted,an alkenyl group which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substituted,a heterocyclic group which may be substituted, a —B¹′—R⁵ group (whereinB¹ is O or S, and R⁵ is a hydrogen atom, an alkyl group which may besubstituted, an alkenyl group which may be substituted, an alkynyl groupwhich may be substituted, a cycloalkyl group which may be substituted, acycloalkenyl group which may be substituted, an aryl group which may besubstituted or a heterocyclic group which may be substituted), an aminogroup which may be substituted or —N═CR⁶R⁷ (wherein each of R⁶ and R⁷which are independent of each other, is a hydrogen atom, an alkyl groupwhich may be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted or a heterocyclic group which may besubstituted); and

[0040] each of Y and Z which are independent of each other, is anitrogen atom or C—R⁸ {wherein R⁸ is a hydrogen atom, a halogen atom, analkyl group which may be substituted, an alkenyl group which may besubstituted, an alkynyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted, an aryl group which may be substituted, a heterocyclicgroup which may be substituted, a —B²—R⁹ group (wherein B^(2,) is CO,COO, O, OCO or S, and R⁹ is a hydrogen atom, an alkyl group which may besubstituted, an alkenyl group which may be substituted, an alkynyl groupwhich may be substituted, a cycloalkyl group which may be substituted, acycloalkenyl group which may be substituted, an aryl group which may besubstituted or a heterocyclic group which may be substituted), an aminogroup which may be substituted, a cyano group or a nitro group).

[0041] Among the compounds of the above formula (I), the compounds ofthe above formula (I′) are more excellent as active ingredients forpreventive or therapeutic medicines for diabetes. No pharmaceuticalcompositions containing the compound of the formula (I′) haveconventionally been known. Among the compounds of the formula (I′), morepreferred compounds are mentioned below.

[0042] (i) Compounds of the formula (I′) wherein R² is an amino groupwhich may be substituted.

[0043] (ii) Compounds of the formula (I′) wherein R² is an amino groupwhich may be substituted, and each of R⁸ and R¹⁰ is a hydrogen atom.

[0044] (iii) Compounds of (ii) wherein the amino group which may besubstituted represented by R² is a —NR^(c)R^(d) group {wherein each ofR^(c) and R^(d) which are independent of each other, is a hydrogen atom,a —O—R⁵ group (wherein R⁵ is a hydrogen atom, an alkyl group which maybe substituted, an alkenyl group which may be substituted, an alkynylgroup which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted or a heterocyclic group which may besubstituted), an alkyl group which may be substituted, an alkenyl groupwhich may be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted or aheterocyclic group which may be substituted, or R^(c) and R^(d) togetherform a ring}.

[0045] (iv) Compounds of the formula (I′) wherein G is CN, CO₂R⁴(wherein R⁴ is a hydrogen atom, an alkyl group which may be substituted,an alkenyl group which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substitutedor a heterocyclic group which may be substituted), CHO, SO₂NR^(a)R^(b)(wherein each of R^(a) and R^(b) which are independent of each other, isa hydrogen atom, a hydroxyl group, an alkoxy group, an alkyl group whichmay be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted or aheterocyclic group which may be substituted, or R^(a) and R^(b) togetherform a ring) or CONR^(a′)R^(b′) (wherein each of R^(a′) and R^(b′) whichare independent of each other, is a hydroxyl group, an alkoxy group, analkyl group which may be substituted, an alkenyl group which may besubstituted, an alkynyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted, an aryl group which may be substituted or a heterocyclicgroup which may be substituted, or R^(a′) and R^(b′) together form aring).

[0046] (v) Compounds of the formula (I′) wherein G is CN, NO₂, CO₂R⁴(wherein R⁴ is a hydrogen atom, an alkyl group which may be substituted,an alkenyl group which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substitutedor a heterocyclic group which may be substituted), CHO, C—SO₂NR^(a)R^(b)(wherein each of R^(a) and R^(b) which are independent of each other, isa hydrogen atom, a hydroxyl group, an alkoxy group, an alkyl group whichmay be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted or aheterocyclic group which may be substituted, or R^(a) and R^(b) togetherform a ring) or CONR^(a′)R^(b′) (wherein each of R^(a′) and R^(b′) whichare independent of each other, is a hydroxyl group, an alkoxy group, analkyl group which may be substituted, an alkenyl group which may besubstituted, an alkynyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted, an aryl group which may be substituted or a heterocyclicgroup which may be substituted, or R^(a′) and R^(b′) together form aring); and

[0047] R¹ is a —O—R⁵ group (wherein R⁵ is a hydrogen atom, an alkylgroup which may be substituted, an alkenyl group which may besubstituted, an alkynyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted, an aryl group which may be substituted or a heterocyclicgroup which may be substituted) or a —S—R⁵ group (R⁵ is an alkyl groupwhich may be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted or a heterocyclic group which may besubstituted).

[0048] Each of the alkyl group which may be substituted, the alkenylgroup which may be substituted, the alkynyl group which may besubstituted, the cycloalkyl group which may be substituted, thecycloalkenyl group which may be substituted, the aryl group which may besubstituted and the heterocyclic group which may be substituted in eachof the substituents represented by each of R^(c) and R^(d) in the—NR^(c)R^(d) group in the above formula (iii) is as defined for each ofthe substituents in the compound of the formula (I). Further, as the—NR^(c)R^(d) group, a substitutable alkylamino group, a substitutabledialkylamino group, an alkylcarbonylamino group, a substitutablealkynylamino group, a cycloalkylamino group or a substitutable arylaminogroup is preferred, and a substitutable alkylamino group or asubstitutable arylamino group is more preferred. The substitutablealkylamino group may, for example, be a benzylamino group, a4-nitrobenzylamino group, a 4-pyridylmethylamino group, a3-pyridylmethylamino group, a 2-pyridylmethylamino group, adioxolanylmethylamino group, a pyranylmethylamino group, a methylaminogroup, an ethylamino group or a dimethylamino group. The substitutablearylamino group may, for example, be a phenylamino group, a4-cyanophenylamino group, a 3-cyanophenylamino group, a4-chlorophenylamino group, a 2-chlorophenylamino group, a4-methylphenylamino group, a 3-methylphenylamino group, a2-methylphenylamino group, a 4-nitrophenylamino group or a3-nitrophenylamino group.

[0049] The preventive or therapeutic medicines for diabetes of thepresent invention are usually used in the form of a commonpharmaceutical preparation. The pharmaceutical preparation is preparedby using a commonly used diluent or excipient such as a bulking agent,an extender, a binding agent, a moisture-imparting agent, adisintegrator, a surfactant or a lubricant. As the pharmaceuticalpreparation, various forms may be selected depending upon the purpose oftreatment, and a tablet, a pill, a powder, a dust, a granule, a capsule,a suppository, a solution, a suspension, an emulsion, an injection (suchas a solution or a suspension), a spray, an aerosol, a cream, anointment, a lotion or a transdermal agent (a patch, a matrix or a tape)may be mentioned as examples.

[0050] To form the medicine into a tablet, carriers which haveconventionally been known in this field can be used widely, and theymay, for example, be excipients such as lactose, sucrose, sodiumchloride, glucose, urea, starch, calcium carbonate, kaolin, crystallinecellulose and silicic acid, binding agents such as water, ethanol,propanol, simple syrup, a glucose solution, a starch solution, a gelatinsolution, carboxymethyl cellulose, Shellac, methyl cellulose, potassiumphosphate and polyvinyl pyrrolidone, disintegrators such as driedstarch, sodium alginate, an agar powder, a laminaran powder, sodiumhydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fattyacid esters, sodium lauryl sulfate, monoglyceryl stearate, starch andlactose, disintegration inhibitors such as sucrose, stearin, cacaobutter and hydrogenated oil, absorption stimulators such as a quaternaryammonium base and sodium lauryl sulfate, moisturizers such as glycerinand starch, absorbents such as starch, lactose, kaolin, bentonite andcolloidal silicate, and lubricants such as purified talc, a stearate, aboric acid powder and polyethylene glycol. Further, a tablet may be atablet having a common coating applied thereto as the case requires,such as a sugar-coated tablet, a gelatin-coated tablet, anenteric-coated tablet or a film-coated tablet, or a double tablet or amultilayer tablet.

[0051] To form the medicine into a pill, carriers which haveconventionally been known in this field can be used widely, and theymay, for example, be excipients such as glucose, lactose, starch, cacaobutter, hydrogenated vegetable oil, kaolin and talc, binding agents suchas powdered acacia, powdered tragacanth, gelatin and ethanol anddisintegrators such as laminaran agar.

[0052] To form the medicine into a suppository, conventionally knowncarriers can be used widely, and they may, for example, be polyethyleneglycol, cacao butter, higher alcohols, higher alcohol esters, gelatinand semi-synthetic glyceride.

[0053] To prepare an injection, a solution, an emulsion or a suspensionis sterilized, and is preferably isotonic with the blood, and to formthe medicine into a solution, an emulsion or a suspension, all thediluents which are commonly used in this field can be used, and theymay, for example, be water, a lactic acid aqueous solution, ethylalcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylatedisostearyl alcohol and polyoxyethylene sorbitan fatty acid esters. Inthis case, salt, glucose or glycerin in an amount adequate to prepare anisotonic solution may be incorporated in the pharmaceutical preparation,and a common solubilizing agent, buffer, soothing agent or the like maybe added thereto. Further, as the case requires, a colorant, apreservative, a fragrant material, a flavoring agent, a sweetener oranother pharmaceutical agent may be incorporated in the pharmaceuticalpreparation.

[0054] The amount of the compound of the above formula (I) to becontained in the therapeutic medicine for diabetes of the presentinvention is not particularly limited and may optionally be selectedfrom a wide range, but it is usually from 1 to 70 wt %, preferably from5 to 50 wt % in the entire composition.

[0055] The administration method of the preventive or therapeuticmedicines for diabetes of the present invention is not particularlylimited, and they are orally or parenterally administered by a methoddepending upon the form of the preparation, the age, the sex or otherconditions of the patient and the degree of the disease. For example,for oral administration, a tablet, a pill, a solution, a suspension, anemulsion, a granule or a capsule may, for example, be mentioned as apreferred form. For parenteral administration, the medicine may beadministered in the form of e.g. a topical agent, an injection, atransdermal agent, a transnasal formulation, a pulmonary deliveryformulation or a suppository. In the case of an injection, it ispreferred that the medicine is intravenously administered by itself oras mixed with a conventional fluid replacement such as glucose or aminoacids, or as the case requires, it is intramuscularly, intradermally,subcutaneously or intraperitoneally administered by itself. Further, inthe case of a suppository, it is preferred that the medicine isadministered in rectum. The dose of the preventive or therapeuticmedicines for diabetes of the present invention is optionally selecteddepending upon e.g. the dose regimen, the age, the sex or otherconditions of the patient and the degree of disease, and usually theamount of the compound of the above formula (I) as an active ingredientis preferably from about 0.05 to about 50 mg per kg of the body weightper day, and the medicine may be administered once or several times aday. Further, it is preferred that the active ingredient is contained inan amount of from 1 to 1,000 mg in the administration unit form.

[0056] The compounds of the above formula (I) and their salts can beproduced by a process for producing known analogous compounds, or amethod in accordance therewith, and as preferred embodiments, thefollowing Preparation Methods [1] to [5] will be exemplified.

[0057] [1] Preparation Method 1

[0058] A method for producing the compound of the above formula (I) byreacting a compound of the formula (II):

[0059] [wherein R is R¹ or R² in the formula (I), A is as defined above,D is a cyano group or an alkoxycarbonyl group, and L is a leavinggroup], with a compound of the formula (III):

[0060] [wherein X, Y and Z are as defined above]. As the leaving grouprepresented by L in the formula (II), various ones may be mentioned, anda halogen atom, a —OR⁵ group, a —SR⁵ group or a dialkylamino group ispreferred (R⁵ is as defined above).

[0061] The reaction of the Preparation Method 1 may be carried out inthe presence of a proper solvent. The specific solvent used may, forexample, be an alcohol such as methanol, ethanol, propanol or butanol;an aromatic hydrocarbon such as benzene, toluene or xylene; an aliphatichydrocarbon such as pentane, hexane, heptane, petroleum ether, ligroinor petroleum benzine; an ether such as diethyl ether, dipropyl ether,dibutyl ether, tetrahydrofuran or dioxane; a nitrile such asacetonitrile or propionitrile; an acid amide such as dimethylformamideor dimethylacetamide; a sulfoxide such as dimethylsulfoxide; a sulfonesuch as sulfolane; a phosphate amide such as hexamethylphosphoramide; ora halogenated hydrocarbon such as chloroform, dichloromethane, carbontetrachloride or 1,2-dichloroethane, or a mixed solvent thereof.

[0062] In the Preparation Method 1, the reaction is carried outpreferably in the presence of a base in some cases.

[0063] The specific base used may, for example, be an organic base suchas triethylamine, pyridine, piperidine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkalimetal such as lithium, sodium or potassium; a carbonate of an alkalimetal such as lithium carbonate, sodium carbonate or potassiumcarbonate; a hydrogencarbonate of an alkali metal such as lithiumhydrogencarbonate, sodium hydrogencarbonate or potassiumhydrogencarbonate; a hydride of an alkali metal such as lithium hydride,sodium hydride or potassium hydride; or n-butylithium, lithiumdiisopropylamide or sodium amide.

[0064] The reaction of the Preparation Method 1 is carried out usuallyat a reaction temperature of from 0 to 150° C., preferably at a reactiontemperature of from 10 to 100° C. The reaction time is usually from 0.1to 48 hours.

[0065] In the Preparation Method 1, the compound of the formula (III)may be used in an amount of from 0.8 to 2 equivalents, preferably from 1to 1.5 equivalents, per 1 mol of the compound of the above formula (II).

[0066] In the Preparation Method 1, various reaction conditions mayoptionally be combined with one another. Further, such various reactionconditions include reaction conditions in a usual range and reactionconditions in a preferred range, and they may also be optionallyselected and combined with one another.

[0067] [2] Preparation Method 2

[0068] A method for producing the compound of the above formula (I) byreacting a compound of the formula (I-1):

[0069] [wherein either one of R^(1′) and R^(2′) is an amino group, OH orSH; and the other is a hydrogen atom, a halogen atom, an alkyl groupwhich may be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted, a heterocyclic group which may besubstituted, a —B¹—R⁵ group (wherein B¹ and R⁵ are as defined above), anamino group which may be substituted or —N═CR⁶R⁷ (wherein R⁶ and R⁷ areas defined above); and A, X, Y and Z are as defined above], with acompound of the formula (IV): R′—L′ [wherein R′ is an alkyl group whichmay be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted, a heterocyclic group which may besubstituted or a —B^(1″)—R^(5′) group (wherein B^(1″) is CO or SO₂, andR^(5′) is an alkyl group which may be substituted, an alkenyl groupwhich may be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted or aheterocyclic group which may be substituted); and L′ is a leavinggroup]. As the leaving group represented by L′ in the formula (IV),various ones may be mentioned, and a halogen atom, a methanesulfonyloxygroup or a para-toluenesulfonyloxy group is preferred.

[0070] The reaction of the Preparation Method 2 may be carried out inthe presence of a proper solvent. The specific solvent used may, forexample, be an aromatic hydrocarbon such as benzene, toluene or xylene;an aliphatic hydrocarbon such as pentane, hexane, heptane, petroleumether, ligroin or petroleum benzine; an ether such as diethyl ether,dipropyl ether, dibutyl ether, tetrahydrofuran or dioxane; a nitrilesuch as acetonitrile or propionitrile; an acid amide such asdimethylformamide or dimethylacetamide; a sulfoxide such asdimethylsulfoxide; a sulfone such as sulfolane; a phosphate amide suchas hexamethylphosphoramide; or a halogenated hydrocarbon such aschloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane,or a mixed solvent thereof.

[0071] In the Preparation Method 2, the reaction is carried outpreferably in the presence of a base, so as to carry out the reactionefficiently. The specific base used may, for example, be an organic basesuch as triethylamine, pyridine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkalimetal such as lithium, sodium or potassium; a carbonate of an alkalimetal such as lithium carbonate, sodium carbonate or potassiumcarbonate; a hydrogencarbonate of an alkali metal such as lithiumhydrogencarbonate, sodium hydrogencarbonate or potassiumhydrogencarbonate; a hydride of an alkali metal such as lithium hydride,sodium hydride or potassium hydride; or n-butylithium, lithiumdiisopropylamide or sodium amide.

[0072] The reaction of the Preparation Method 2 is carried out usuallyat a reaction temperature of from −70 to 200° C., preferably at areaction temperature of from −10 to 150° C. The reaction time is usuallyfrom 0.1 to 48 hours.

[0073] In the Preparation Method 2, the compound of the formula (IV) maybe used in an amount of from 0.8 to 2 equivalents, preferably from 1 to1.5 equivalents, per 1 mol of the compound of the above formula (I-1).

[0074] In the Preparation Method 2, various reaction conditions mayoptionally be combined with one another. Further, such various reactionconditions include reaction conditions in a usual range and reactionconditions in a preferred range, and they may also be optionallyselected and combined with one another.

[0075] [3] Preparation Method 3

[0076] A method for producing the compound of the above formula (I) byreacting a compound of the formula (I-2):

[0077] [wherein either one of R^(1″) and R^(2″) is OH, and the other isa hydrogen atom, a halogen atom, an alkyl group which may besubstituted, an alkenyl group which may be substituted, an alkynyl groupwhich may be substituted, a cycloalkyl group which may be substituted, acycloalkenyl group which may be substituted, an aryl group which may besubstituted, a heterocyclic group which may be substituted, a —B¹—R⁵group (wherein B¹ and R⁵ are as defined above), an amino group which maybe substituted or —N═CR⁶R⁷ (wherein R⁶ and R⁷ are as defined above); andA, X, Y and Z are as defined above], with a halogenating agent.

[0078] The halogenating agent used in the reaction of the PreparationMethod 3 may, for example, be phosphorus pentachloride, phosphorusoxychloride, phosphorus trichloride, thionyl chloride, oxalyl chlorideor phenylphosphonate dichloride, and its amount is from 1 to 10equivalents, preferably from 1 to 5 equivalents, per 1 mol of thecompound of the above formula (I-2).

[0079] The reaction of the Preparation Method 3 may be carried out inthe presence of a proper solvent. The specific solvent used may, forexample, be an aromatic hydrocarbon such as benzene, toluene or xylene;an aliphatic hydrocarbon such as pentane, hexane, heptane, petroleumether, ligroin or petroleum benzine; an ether such as diethyl ether,dipropyl ether, dibutyl ether, tetrahydrofuran or dioxane; or ahalogenated hydrocarbon such as chloroform, dichloromethane, carbontetrachloride or 1,2-dichloroethane, or a mixed solvent thereof. Thereaction is carried out preferably in the system in which no water ispresent.

[0080] In the Preparation Method 3, the reaction is carried outpreferably in the presence of a base, so as to carry out the reactionefficiently. The specific base used may, for example, be an organic basesuch as triethylamine, pyridine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline.

[0081] The reaction of the Preparation Method 2 is carried out usuallyat a reaction temperature of from −30 to 200° C., preferably at areaction temperature of from 0 to 150° C. The reaction time is usuallyfrom 0.1 to 48 hours.

[0082] In the Preparation Method 3, various reaction conditions mayoptionally be combined with one another. Such various reactionconditions include reaction conditions in a usual range and reactionconditions in a preferred range, and they may also be optionallyselected and combined with one another.

[0083] [4] Preparation Method 4

[0084] A method for producing the compound of the above formula (I) byreacting a compound of the formula (I-3):

[0085] [wherein either one of R^(1′″) and R^(2′″) is a halogen atom, a—B^(1′″)—R^(5″) group (wherein B^(1′″) is O, OSO₂, S or SO₂, and R^(5′)is an alkyl group which may be substituted or an aryl group which may besubstituted) or a dialkylamino group, and the other is a hydrogen atom,a halogen atom, an alkyl group which may be substituted, an alkenylgroup which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substituted,a heterocyclic group which may be substituted, a —B¹—R⁵ group (whereinB¹ and R⁵ are as defined above), an amino group which may be substitutedor —N═CR⁶R⁷ [wherein R⁶ and R⁷ are as defined above); and A, X, Y and Zare as defined above], with a compound of the formula (V): R″—B′″(wherein R″ is an alkyl group which may be substituted, an alkenyl groupwhich may be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted or aheterocyclic group which may be substituted, and B′″ is an amino group,OH or SH].

[0086] The reaction of the Preparation Method 4 may be carried out inthe presence of a proper solvent. The specific solvent used may, forexample, be an aromatic hydrocarbon such as benzene, toluene or xylene;an aliphatic hydrocarbon such as pentane, hexane, heptane, petroleumether, ligroin or petroleum benzine; an ether such as diethyl ether,dipropyl ether, dibutyl ether, tetrahydrofuran or dioxane; a nitrilesuch as acetonitrile or propionitrile; an acid amide such asdimethylformamide or dimethylacetamide; a sulfoxide such asdimethylsulfoxide; a sulfone such as sulfolane; a phosphate amide suchas hexamethylphosphoramide; or a halogenated hydrocarbon such aschloroform, dichloromethane, carbon tetrachloride or 1,2-dichloroethane,or a mixed solvent thereof.

[0087] In the Preparation Method 4, the reaction is carried outpreferably in the presence of a base, so as to carry out the reactionefficiently. The specific base used may, for example, be an organic basesuch as triethylamine, pyridine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; an alkalimetal such as lithium, sodium or potassium; a carbonate of an alkalimetal such as lithium carbonate, sodium carbonate or potassiumcarbonate; a hydrogencarbonate of an alkali metal such as lithiumhydrogencarbonate, sodium hydrogencarbonate or potassiumhydrogencarbonate; a hydride of an alkali metal such as lithium hydride,sodium hydride or potassium hydride; or n-butylithium, lithiumdiisopropylamide or sodium amide.

[0088] The reaction of the Preparation Method 4 is carried out usuallyat a reaction temperature of from −70 to 150° C., preferably at areaction temperature of from −10 to 100° C. The reaction time is usuallyfrom 0.1 to 48 hours.

[0089] In the Preparation Method 4, the compound of the formula (V) maybe used in an amount of from 0.8 to 2 equivalents, preferably from 1 to1.5 equivalents, per 1 mol of the compound of the above formula (I-3).

[0090] In the Preparation Method 3, various reaction conditions mayoptionally be combined with one another. Further, such various reactionconditions include reaction conditions in a usual range and reactionconditions in a preferred range, and they may also be optionallyselected and combined with one another.

[0091] [5] Preparation Method 5

[0092] A method for producing the compound of the above formula (I) byreacting a compound of the formula (I-4):

[0093] [wherein either one of R^(1″″) and R^(2″″) is an amino group, andthe other is a hydrogen atom, a halogen atom, an alkyl group which maybe substituted, an alkenyl group which may be substituted, an alkynylgroup which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted, a heterocyclic group which may besubstituted, a —B¹—R⁵ group (wherein B¹ and R⁵ are as defined above), anamino group which may be substituted or —N═CR⁶R⁷ (wherein R⁶ and R⁷ areas defined above); and A, X, Y and Z are as defined above], with acompound of the formula (VI): R⁶R⁷C═O [wherein R⁶ and R⁷ are as definedabove].

[0094] The reaction of the Preparation Method 5 may be carried out inthe presence of a proper solvent. The specific solvent used may, forexample, be an alcohol such as methanol, ethanol, propanol or butanol;an aromatic hydrocarbon such as benzene, toluene or xylene; an aliphatichydrocarbon such as pentane, hexane, heptane, petroleum ether, ligroinor petroleum benzine; an ether such as diethyl ether, dipropyl ether,dibutyl ether, tetrahydrofuran or dioxane; a nitrile such asacetonitrile or propionitrile; an acid amide such as dimethylformamideor dimethylacetamide; a sulfoxide such as dimethylsulfoxide; a sulfonesuch as sulfolane; a phosphate amide such as hexamethylphosphoramide; ora halogenated hydrocarbon such as chloroform, dichloromethane, carbontetrachloride or 1,2-dichloroethane, or a mixed solvent thereof.

[0095] In the Preparation Method 5, the reaction is carried outpreferably in the presence of a base, so as to carry out the reactionefficiently. The specific base used may, for example, be an organic basesuch as triethylamine, pyridine, N-methylmorpholine,1,8-diazabicyclo[5,4,0]-7-undecene or N,N-dimethylaniline; a carbonateof an alkali metal such as lithium carbonate, sodium carbonate orpotassium carbonate; or a hydrogencarbonate of an alkali metal such aslithium hydrogencarbonate, sodium hydrogencarbonate or potassiumhydrogencarbonate.

[0096] In the Preparation Method 5, the reaction is carried outpreferably in the presence of a dehydrating agent such as molecularsieves, so as to carry out the reaction efficiently. Further, a propersolvent may be used to remove formed moisture from the reaction systemby azeotropy.

[0097] The reaction of the Preparation Method 5 is carried out usuallyat a reaction temperature of from −30 to 150° C., preferably at areaction temperature of from 0 to 100° C. The reaction time is usuallyfrom 0.1 to 48 hours.

[0098] In the Preparation Method 5, the compound of the formula (VI) maybe used in an amount of from 0.8 to 2 equivalents, preferably from 1 to1.5 equivalents, per 1 mol of the compound of the above formula (I-3).

[0099] In the Preparation Method 5, various reaction conditions mayoptionally be combined with one another. Further, such various reactionconditions include reaction conditions in a usual range and reactionconditions in a preferred range, and they may also be optionallyselected and combined with one another.

[0100] The compounds of the above formula (I) and their salts may beproduced by any one of the above Preparation Methods [1] to [5] or acombination thereof.

[0101] The compounds of the above formula (I) may form salts by aconventional method. Further, the compounds of the above formula (I) mayform inner salts in some cases.

[0102] Among the compounds of the above formula (I) and their salts,compounds having a carboxyl group in their molecular structures andtheir salts may be produced by hydrolyzing corresponding esters under anacid or alkali condition.

[0103] Among the compounds of the above formula (I) and their salts,compounds of the formula (I′) and their salts may be produced by one ofthe following Preparation Methods [A] to [G] or a combination of thesePreparation Methods, in accordance with the above Preparation Methods 1to 5.

[0104] [A]

[0105] Among the compounds of the above formula (I′) and their salts,compounds of the formula (I′-1) and their salts:

[0106] [wherein R¹, R⁸, R¹⁰ and G are as defined in the above formula(I′)], can be produced by reacting a compound of the formula (VII):

[0107] [wherein R¹ and G are as defined above; D is an alkoxycarbonylgroup; and L is a halogen atom, a —OR⁵ group, a —SR⁵ group or adialkylamino group (R⁵ is as defined above)], with a compound of theformula (VIII):

[0108] [wherein R⁸ and R¹⁰ are as defined above]. The Preparation Method[A] is in accordance with the Preparation Method 1, and various reactionconditions in the Preparation Method 1 can be applied.

[0109] [B]

[0110] Among the compounds of the above formula (I′) and their salts,compounds of the formula (I′-2) and their salts:

[0111] [wherein R¹, R⁸ and R¹⁰ are as defined in the above formula (I′);and G′ is CN, NO₂, SO₂NR^(a)R^(b) (wherein R^(a) and R^(b) are asdefined above) or CONR^(a)R^(b) (wherein R^(a) and R^(b) are as definedabove)], can be produced by reacting a compound of the formula (VII′):

[0112] [wherein R¹ and G′ are as defined above; and L is a halogen atom,a —OR⁵ group, a —SR⁵ group or a dialkylamino group (R⁵ is as definedabove)], with a compound of the formula (VIII):

[0113] [wherein R⁸ and R¹⁰ are as defined above]. The Preparation Method[B] is in accordance with the Preparation Method 1, and various reactionconditions in the Preparation Method 1 can be applied.

[0114] [C]

[0115] Among the compounds of the above formula (I′) and their salts,compounds of the formula (I′-3) and their salts:

[0116] [wherein R¹, R⁸, R¹⁰ and G are as defined in the above formula(I′)], can be produced by reacting the compound of the formula (I′-1)produced by the method as defined in the Preparation Method [A] with ahalogenating agent. The Preparation Method [C] is in accordance with thePreparation Method 3, and various reaction conditions in the PreparationMethod 3 can be applied.

[0117] [D]

[0118] Among the compounds of the above formula (I′) and their salts,compounds of the formula (I′-4) and their salts:

[0119] [wherein R¹, R⁸, R¹⁰ and G are as defined in the above formula(I′); and R⁵ is an alkyl group which may be substituted, an alkenylgroup which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substitutedor a heterocyclic group which may be substituted], can be produced byreacting the compound of the formula (I′-1) produced by the method asdefined in the Preparation Method [A] with a compound of the formula(IX): R^(5′)-L′ [wherein R^(5′) is as defined above; and L′ is a halogenatom, a methanesulfonyloxy group or a para-toluenesulfonyloxy group].The Preparation Method [D] is in accordance with the Preparation Method2, and various reaction conditions in the Preparation Method 2 can beapplied.

[0120] [E]

[0121] Among the compounds of the above formula (I′) and their salts,compounds of the formula (I′-5) and their salts:

[0122] [wherein R¹, R⁸, R¹⁰ and G are as defined in the above formula(I′); and Q is a substituted amino group], can be produced also byreacting the compound of the formula (I′-3) produced by the method asdefined in the Preparation Method [C] with a compound of the formula(IV-1): H-Q [wherein Q is a substituted amino group]. The PreparationMethod [E] is in accordance with the Preparation Method 4, and variousreaction conditions in the Preparation Method 4 can be applied.

[0123] [F]

[0124] Further, the compounds of the formula (I′-5) and their salts canbe produced also by reacting the compound of the formula (I′-4) producedby the method as defined in the Preparation Method [D] with the compoundof the formula (IV-1). The Preparation Method [F] is in accordance withthe Preparation Method 4, and various reaction conditions in thePreparation Method 4 can be applied.

[0125] [G]

[0126] Further, among the compounds of the above formula (I′-5) andtheir salts, compounds of the formula (I′-5′) and their salts:

[0127] [wherein R¹, R⁸, R¹⁰ and Q are as defined in the above formula(I′-5); and G′ is as defined in the above formula (I′-2)], can beproduced by reacting the compound of the formula (I′-2) produced by themethod as defined in the Preparation Method [B] with a compound of theformula (IV-2): L′-J [wherein J is a substituent of the substitutedamino group represented by Q; and L′ is a halogen atom, amethanesulfonyloxy group or a para-toluenesulfonyloxy group]. ThePreparation Method [G] is in accordance with the Preparation Method 2,and various reaction conditions in the Preparation Method 2 can beapplied.

EXAMPLES

[0128] Now, Examples (Preparation Examples and Test Examples) of thepresent invention will be described, however, the present invention isby no means restricted thereto.

Preparation Example 1

[0129] Preparation of7-benzylamino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile(compound No. 2)

[0130] (1) 10.3 g of bismethylthio methylenepropane dinitrile, 5.0 g of3-aminopyrazole and 250 ml of ethanol were stirred under reflux withheating for about 6 hours and then cooled to room temperature, and theprecipitated crystals were collected by filtration. The collectedcrystals were washed with ethanol and then dried to obtain 10.9 g of7-amino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compoundNo. 1) having a melting point of at least 240° C.

[0131] (2) 100 mg of sodium hydride (60%) was added to 500 mg of7-amino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile and 8 ml ofDMF, followed by stirring at room temperature for about 10 minutes, andthen 420 mg of benzyl bromide was added thereto, followed by stirring atabout 50° C. for about 2 hours. After completion of the reaction, thereaction mixture was cooled to room temperature, about 50 ml of waterwas added thereto, and the precipitated crystals were collected byfiltration, washed with water and dried to obtain crude crystals. Thecrude crystals were purified by silica gel column chromatography toobtain 570 mg of7-benzylamino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile(compound No. 2) having a melting point of 165° C.

Preparation Example 2

[0132] Preparation of7-benzyloxy-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile(Compound No. 51)

[0133] (1) 3.0 g of 2-cyano-3,3-bismethylthio-2-propenoic acid methylester, 1.3 g of 3-aminopyrazole and 20 ml of ethanol were stirred underreflux with heating for about 2.5 hours and then cooled to roomtemperature, and the precipitated crystals were collected by filtration.The collected crystals were washed with ethanol and then dried to obtain1.69 g of 7-hydroxy-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile(compound No. 49) having a melting point of over 250° C.

[0134] (2) 80 mg of sodium hydride (60%) was added to 400 mg of7-hydroxy-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile and 6 mlof DMF, followed by stirring at room temperature for about 10 minutes,and then 350 mg of benzyl bromide was added thereto, followed bystirring at about 50° C. overnight. After completion of the reaction,the reaction mixture was cooled to room temperature, about 50 ml ofwater was added thereto, and the precipitated crystals were collected byfiltration, washed with water and dried to obtain crude crystals. Thecrude crystals were purified by silica gel column chromatography toobtain 490 mg of7-benzyloxy-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile(compound No. 51) having a melting point of 194° C.

Preparation Example 3

[0135] Preparation of7-(4-pyridylmethyl)amino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile(Compound No. 3)

[0136] (1) A mixture comprising 2.15 g of7-hydroxy-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compoundNo. 49), 1.3 g of N,N-dimethylaniline and 5 ml of phosphorus oxychloridewas stirred under reflux with heating for about 3 hours. After thecompletion of the reaction, the reaction mixture was cooled to roomtemperature, and poured into ice water, followed by stirring. Theprecipitated crystals were collected by filtration, washed with waterand dried to obtain crude crystals. The crude crystals were purified bysilica gel column chromatography to obtain 2.17 g of7-chloro-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compoundNo. 62) having a melting point of from 201 to 202° C.

[0137] (2) A mixture comprising 460 mg of 4-picolylamine, 430 mg oftriethylamine and 1 ml of acetonitrile was dropwise added to 950 mg of7-chloro-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile and 20 mlof acetonitrile under cooling with ice, followed by stirring for about 1hour. After completion of the reaction, about 80 ml of water was addedthereto, and the precipitated crystals were collected by filtration,washed with water and dried to obtain crude crystals. The crude crystalswere purified by silica gel column chromatography to obtain 970 mg of7-(4-pyridylmethyl)amino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile(compound No. 3) having a melting point of from 153 to 154° C.

Preparation Example 4

[0138] Preparation of7-furfurylamino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile(Compound No. 78)

[0139] 200 mg of7-chloro-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile (compoundNo. 62) and 100 mg of furfurylamine were reacted in 5 ml of THF in thepresence of 110 mg of triethylamine for about 30 minutes, then about 30ml of water was added thereto, and the precipitated crystals werecollected by filtration, washed with water and dried to obtain crudecrystals. The crude crystals were washed with ether to obtain 180 mg of7-furfurylamino-5-methylthiopyrazolo[1,5-a]pyrimidine-6-carbonitrile(compound No. 78) having a melting point of 110° C.

[0140] Compounds of the above formula (I) produced in PreparationExamples 1 to 4 and by methods in accordance with the above PreparationMethods 1 to 5 are shown in the following Tables 1 to 26. TABLE 1Compound Physical No. Structural Formula properties 1

m.p. >240° C. 2

m.p.: 165° C. 3

m.p.: 153-154° C. 4

m.p.: 192° C. 5

m.p.: 190° C. 6

m.p.: 139° C. 7

m.p. >280° C. 8

m.p.: 157-158° C. 9

m.p.: 132-133° C.

[0141] TABLE 2 Com- pound Physical No. Structural Formula properties 10

m.p.: 63-64° C. 11

m.p.: 121-122° C. 12

m.p.: 107° C. 13

m.p.: 184-185° C. 14

m.p.: 216° C. 15

m.p.: 133° C. 16

m.p.: 215° C. 17

m.p.: 144° C. 18

m.p.: 212-213° C.

[0142] TABLE 3 Com- pound Physical No. Structural Formula properties 19

m.p.: 87-88° C. 20

m.p.: 164-165° C. 21

m.p.: 141° C. 22

m.p.: 169° C. 23

m.p.: 171° C. 24

m.p.: >250° C. 25

m.p.: >250° C. 26

m.p.: 135° C. 27

m.p.: 143° C.

[0143] TABLE 4 Compound Physical No. Structural Formula properties 28

m.p.: 125° C. 29

m.p.: 165° C. 30

m.p.: 195° C. 31

m.p.: 167° C. 32

m.p.: 155° C. 33

m.p.: 160° C. 34

m.p.: 188° C. 35

m.p.: >250° C. 36

m.p.: 154° C.

[0144] TABLE 5 Compound Physical No. Structural Formula properties 37

m.p.: 211° C. 38

m.p.: 230-233° C. 39

m.p.: 133° C. 40

m.p.: 136° C. 41

m.p.: >250° C. 42

m.p.: 179° C. 43

m.p.: 204° C. 44

m.p.: 233° C. 45

m.p.: >250° C.

[0145] TABLE 6 Compound Physical No. Structural Formula properties 46

m.p.: 172° C. 47

m.p.: 233° C. 48

m.p.: 232° C. 49

m.p. >250° C. 50

m.p.: 159° C. 51

m.p.: 194° C. 52

Solid 53

m.p.: 183° C. 54

m.p. >250° C.

[0146] TABLE 7 Com- pound Physical No. Structural Formula properties 55

m.p.: 184° C. 56

m.p.: 137° C. 57

m.p.: 155-157° C. 58

m.p.: 230-233° C. 59

m.p.: 175° C. 60

m.p.: 162-163° C. 61

m.p.: 163-164° C. 62

m.p.: 201-202° C. 63

m.p.: 195-196° C.

[0147] TABLE 8 Compound Physical No. Structural Formula properties 64

m.p.: 175° C. 65

m.p.: 113° C. 66

m.p. >240° C. 67

m.p.: 112-113.4° C. 68

m.p.: 196-196.4° C. 69

m.p.: 245.6-245.9° C. 70

m.p.: 121-122.2° C. 71

m.p.: 187.8-189.2° C. (decomposition) 72

m.p. >240° C.

[0148] TABLE 9 Compound Physical No. Structural Formula properties 73

m.p.: 114.7-115.2° C. 74

m.p.: 134.5-135° C. 75

m.p.: 258.5-259° C. 76

m.p.: 178.8-179.8° C. 77

m.p.: 90-91.5° C. 78

m.p.: 110° C. 79

m.p.: 118° C. 80

m.p.: 195-196° C. 81

m.p.: 260-263° C.

[0149] TABLE 10 Com- pound Physical No. Structural Formula properties 82

m.p.: 188° C. 83

m.p.: 144-146° C. 84

m.p.: 207° C. 85

m.p. >250 ° C. 86

m.p.: 120-122° C. 87

m.p.: 242° C. 88

m.p.: 163° C. 89

m.p.: 199-201° C. 90

m.p.: 195-198° C.

[0150] TABLE 11 Com- pound Structural Physical No. Formula properties 91

m.p. >250° C. 92

93

94

m.p.: 206° C. (decom- position) 95

m.p.: 142.2-144.2° C. 96

m.p.: 208.5-208.7° C. 97

98

99

[0151] TABLE 12 Compound Physical No. Structural Formula properties 100

101

102

103

m.p.: 270.5-271.3° C. 104

m.p.: 115.8-116.6° C. 105

m.p.: 153.4-155.4° C. 106

m.p.: 214-216° C. (decomposition) 107

m.p.: 137.4-141.4° C. 108

m.p.: 164-165.5° C. (decomposition)

[0152] TABLE 13 Compound Physical No. Structural Formula properties 109

m.p.: 117-118° C. 110

m.p.: 241.7-242.1° C. 111

m.p.: 94-96° C. 112

m.p.: 113.5-118° C. 113

m.p.: 242.0-243.8° C. 114

m.p.: 107.0-108.3° C. 115

m.p.: 129.0-133.4° C. 116

m.p. >300° C. 117

m.p.: 130.5-133.5° C.

[0153] TABLE 14 Compound Physical No. Structural Formula properties 118

m.p.: 160.0-161.6° C. 119

m.p.: 105-113° C. 120

m.p.: 124.5-126.5° C. 121

m.p.: 158.5-160.5° C. 122

Oily matter 123

m.p.: 84.5-85.5° C. 124

Solid 125

m.p.: 136.5-138.5° C. 126

m.p.: 154-155° C.

[0154] TABLE 15 Com- pound Physical No. Structural Formula properties127

m.p.: 132-134° C. 128

m.p.: 162.7-164° C. 129

m.p.: 155-157° C. 130

m.p.: 180.5-181.3° C. 131

m.p.: 175.7-176.4° C. 132

Oily matter 133

m.p.: 126.5-127.5° C. 134

m.p.: 162.5-164.5° C. 135

m.p.: 148.8-149.6° C.

[0155] TABLE 16 Compound Physical No. Structural Formula properties 136

m.p.: 148.3-149.7° C. 137

m.p.: 55-56° C. 138

m.p.: 100.5-101° C. 139

m.p.: 107-108.5° C. 140

m.p.: 56-58° C. 141

m.p.: 111-112° C. 142

m.p.: 120-122° C. 143

m.p.: 55-57° C. 144

m.p.: 98-99° C.

[0156] TABLE 17 Compound Physical No. Structural Formula properties 145

m.p.: 102-103° C. 146

m.p.: 52-54° C. 147

m.p.: 122-123° C. 148

m.p.: 141-142° C. 149

m.p.: 285-288° C. (decomposition) 150

m.p.: 303-306° C. (decomposition) 151

m.p.: 205-208° C. 152

m.p.: >280° C. 153

m.p.: 193-195° C.

[0157] TABLE 18 Com- pound Physical No. Structural Formula properties154

Solid 155

m.p.: 192-194° C. 156

m.p.: 139-142° C. 157

m.p.: 123-125° C. 158

m.p.: 128-130° C. 159

Oily matter 160

m.p.: 118-120° C. 161

m.p.: 275-276° C. 162

m.p.: 161-162° C.

[0158] TABLE 19 Compound Physical No. Structural Formula properties 163

m.p.: 201-202° C. 164

m.p.: 201-202° C. 165

m.p.: 146-148° C. 166

m.p.: 140-141° C. 167

m.p.: 243-244° C. 168

m.p.: 280-281° C. 169

m.p.: 214-215° C. 170

m.p.: 250-256° C. 171

m.p.: 205-206° C.

[0159] TABLE 20 Com- pound Physical No. Structural Formula properties172

m.p.: 177-178° C. 173

m.p.: 167-169° C. 174

m.p.: 129-130° C. 175

m.p.: 191-192° C. 176

m.p. >250° C. 177

m.p.: 175-176° C. 178

m.p.: 214-215° C. 179

m.p. >250° C. 180

m.p.: 142° C.

[0160] TABLE 21 Compound Physical No. Structural Formula properties 181

m.p.: 122° C. 182

m.p.: 125° C. 183

m.p.: 138° C. 184

m.p. >250° C. 185

m.p.: 182-187° C. 186

m.p.: 235-238° C. 187

m.p.: 204-205° C. 188

m.p.: 190-191° C. 189

m.p.: 185-187° C.

[0161] TABLE 22 Compound Physical No. Structural Formula properties 190

m.p.: 155-156° C. 191

m.p.: 174-176° C. 192

m.p. 142-143° C. 193

m.p. >280° C. 194

m.p.: 153-155° C. 195

m.p.: 168-171° C. 196

m.p.: 190-191° C. 197

m.p. >280° C. 198

m.p.: 268-269° C.

[0162] TABLE 23 Compound Physical No. Structural Formula properties 199

m.p.: 260-261° C. 200

m.p. >270° C. 201

m.p.: 241-244° C. 202

m.p.: 250-252° C. 203

m.p.: 192-194° C. 204

m.p.: 182-183° C. 205

m.p.: 214-218° C. 206

m.p.: 138-139° C. 207

m.p.: 185-187° C.

[0163] TABLE 24 Compound Physical No. Structural Formula properties 208

m.p.: 152-153° C. 209

m.p.: 161-161° C. 210

m.p.: 96-97° C. 211

m.p.: 158-159° C. 212

m.p.: 116-120° C. 213

m.p.: 143-144° C. 214

m.p.: 206-208° C. 215

m.p.: 184-185° C. 216

m.p.: 103-104° C.

[0164] TABLE 25 Compound Physical No. Structural Formula properties 217

m.p.: 193-195° C. 218

m.p.: 180-182° C. 219

Solid 220

Solid 221

m.p.: 123° C. 222

m.p.: 114-115° C. 223

m.p.: 156-157° C. 224

m.p.: 178° C. 225

m.p.: 166-168° C.

[0165] TABLE 26 Compound Physical No. Structural Formula properties 226

m.p.: 170° C. 227

m.p.: 106-108° C. 228

m.p.: 102-103° C. 229

m.p.: 223-224° C.

Test Example 1

[0166] Pharmacological Test

[0167] Glucose Uptake Test by L6 Cells

[0168] Each of compounds under test was applied to L6 cells (rat cellsoriginally derived from skeletal muscles) by the following method tomeasure the stimulating effect on glucose uptake. Namely, L6 cells weresuspended in α-minimum essential medium (hereinafter referred to simplyas MEM) containing 10% fetal bovine serum (hereinafter referred tosimply as FBS), and inoculated into a 96-well plastic plate in an amountof 5×10⁴ cells/well and cultivated in an incubator (5% carbon dioxidegas, 37° C. until the cells grew all over the well. Then, the culturemedium was switched to MEM solution containing 2% BS, followed bycultivation further for from 7 to 10 ays (the culture medium wasexchanged every three days) to differentiate the cells into skeletalmuscle cells. Then, the culture medium was replaced with MEM solutionwithout FBS, followed by cultivation for three hours, and then thecompound under test prepared to a treatment concentration (diluted withMEM solution without FBS) was reacted with the skeletal muscle cells at37° C. for 1 hour. The cells were washed with Krebs-Henseleit-Ringerbuffer solution (hereinafter referred to simply as KHR buffer solution),and 2-deoxy-[³H]-glucose was added to the cells in the KHR buffersolution, followed by treatment at 37° C. for 10 minutes. The treatmentsolution was removed, the cells were washed with the KHR buffersolution, then the cells were dissolved in a 1N sodium hydroxidesolution in an appropriate amount, and the [³H] radio activity wasmeasured by means of a liquid scintillation counter (cpm) The percentageof the glucose uptake was represented by the percentage of radioactivity when the compound under test was applied, taking the radioactivity of the control (the MEM solvent alone was applied) as 100%.Each of the compounds as identified in Table 27 was used for treatmentat a concentration of each of 10 μg/ml and 100 Ξg/ml to examine thestimulating effect on glucose uptake. As a result, it was confirmed thatall the tested compounds showed stimulating effects on glucose uptake ofat least 115% at least within a range of from 10 μg/ml to 100 μg/ml.TABLE 27 Treatment concentration Ratio (μg/ml) Compound No. activity (%)10 2, 3, 9, 11, 22, 40, 43, 50, 60, 64, 68, >115 71, 72, 74, 79, 80, 82,105, 112, 118, 120, 121, 122, 126, 131, 133, 135, 136, 138, 144, 161,163, 164, 168, 172, 178, 186, 191, 200, 203, 205, 206, 210, 211, 215,218, 221, 222, 223, 224, 225, 226 100 2, 3, 4, 5, 8, 9, 14, 15, 17, 22,25 >115 27, 28, 29, 40, 43, 46, 47, 48, 50, 53, 68, 71, 83, 108, 118,121, 122, 130, 131, 132, 135, 136, 144, 168, 172, 174, 177, 178, 186,190, 200, 210, 211, 218, 221, 223, 226

Test Example 2

[0169] Beneficial Effect Test

[0170] Test for Hypoglycemic Effect

[0171] Using KK-Ay/Ta mice (purchased from CLEA Japan, Inc.) asspontaneous diabetic type II, the hypoglycemic effect of each ofcompounds under test was confirmed by the following method.

[0172] Male KK-Ay/Ta mice sufficiently preliminarily bred andacclimatized were classified into groups, each consisting of six mice,and each of the compounds under test was administered. Each of thecompounds under test as suspended in 0.5% carboxymethyl cellulose(manufactured by Nacalai Tesque), and each compound was orallyadministered singly in a dose of 50 mg/kg (10 ml/kg) by means of an oralconductor. At the same time, as a group of vehicle control, 0.5%carboxymethyl cellulose was administered in the same volume (10 ml/kg)as for the group of administration of compound under test.

[0173] Collection of blood was carried out by the following methodbefore the administration of each of the compounds under test or thevehicle, and at the time as identified in Table 28 after theadministration. The tail vein of each mouse was shallowly cut by theedge of a razor to cause bleeding in an amount of blood of from 10 to 20μL, and the blood was collected by a micropipet. The collected bloodsamples were immediately mixed with a heparin solution (20 U/ml)(manufactured by Mochida Yakuhin) in the same amount as the respectivecollected blood samples, and subjected to centrifugation at 4° C. for 5minutes (10,000 rpm) by means of a cooling centrifugal machine. Theplasma after the centrifugation was obtained as a sample for bloodglucose level measurement.

[0174] The blood glucose level was measured by means of glucose oxidasemethod, and measured by using a commercially available assay kit(Glucose CII TEST WAKO, manufactured by Wako Pure Chemical Industries,Ltd.). Measurement was carried out on the day after the collection ofblood, and the obtained plasma was stored at −20° C. before themeasurement.

[0175] The blood glucose level at the time of collection of blood wascalculated as the percentage to the blood glucose level beforeadministration of the compound under test, and the hypoglycemic effectof the compound under test was evaluated by comparison with the changeof the blood glucose level (percentage) of the group of vehicle controlat the time of collection of blood. The results are shown in Table 28.The evaluation results of the hypoglycemic effect are considered to havea significant difference compared with the vehicle control by means ofWilcoxon's rank sum test (P≦0.05) TABLE 28 Time for Rate of change Rateof change of Compound collection of blood blood glucose level under testof blood glucose level of vehicle control Compd. No. 3 After 3 hours 78%93% Compd. No. 8 After 6 hours 68% 88% Compd. No. 50 After 3 hours 74%96% Compd. No. 186 After 3 hours 80% 96% Compd. No. 200 After 3 hours79% 96%

INDUSTRIAL APPLICABILITY

[0176] The preventive or therapeutic medicines for diabetes of thepresent invention show stimulating effect on glucose uptake byapplication to skeletal muscle cells only for a short time, andaccordingly they are useful as preventive or therapeutic medicinesparticularly for diabetes; impaired glucose tolerance; various diabeticcomplications such as hyperlipidemia, vascular diseases, retinopathy,nephropathy, neuropathy and hypertension; and obesity.

1. A preventive or therapeutic medicine for diabetes containing as anactive ingredient a fused-heterocyclic compound of the formula (I) orits salt:

[wherein A is a nitrogen atom or C-G (wherein G is CN, NO₂, SO₂R³(wherein R³ is an alkyl group which may be substituted, an alkenyl groupwhich may be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted or aheterocyclic group which may be substituted), CO₂R⁴ (wherein R⁴ is ahydrogen atom, an alkyl group which may be substituted, an alkenyl groupwhich may be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted or aheterocyclic group which may be substituted), CHO, SO₂NR^(a)R^(b)(wherein each of R^(a) and R^(b) which are independent of each other, isa hydrogen atom, a hydroxyl group, an alkoxy group, an alkyl group whichmay be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted or a heterocyclic group which may besubstituted, or R^(a) and R^(b) together form a ring) or CONR^(a)R^(b)(wherein R^(a) and R^(b) are as defined above)}; each of R¹ and R² whichare independent of each other, is a hydrogen atom, a halogen atom, analkyl group which may be substituted, an alkenyl group which may besubstituted, an alkynyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted, an aryl group which may be substituted, a heterocyclicgroup which may be substituted, a —B¹—R⁵ group (wherein B¹ is CO, COO,O, OCO, OSO₂, S, SO or SO₂, and R⁵ is a hydrogen atom, an alkyl groupwhich may be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted or a heterocyclic group which may besubstituted), an amino group which may be substituted or —N═CR⁶R⁷(wherein each of R⁶ and R⁷ which are independent of each other, is ahydrogen atom, an alkyl group which may be substituted, an alkenyl groupwhich may be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted or aheterocyclic group which may be substituted; each of Y and Z which areindependent of each other, is a nitrogen atom or C—R⁸ {wherein R⁸ is ahydrogen atom, a halogen atom, an alkyl group which may be substituted,an alkenyl group which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substituted,a heterocyclic group which may be substituted, a —B²—R⁹ group (whereinB² is CO, COO, O, OCO, OSO₂, S, SO or SO₂, and R⁹ is a hydrogen atom, analkyl group which may be substituted, an alkenyl group which may besubstituted, an alkynyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted, an aryl group which may be substituted or a heterocyclicgroup which may be substituted), an amino group which may besubstituted, a cyano group or a nitro group}, provided that when Y and Zare simultaneously C—R⁸, the two R⁸'s may be the same or different; X isa nitrogen atom or C—R¹⁰ {wherein R¹⁰ is a hydrogen atom, a halogenatom, an alkyl group which may be substituted, an alkenyl group whichmay be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, a —B²—R⁹ group (wherein B² and R⁹ are as definedabove), an amino group which may be substituted, a cyano group or anitro group}; and in a case where Y is C—R⁸, and X is C—R¹⁰ or Z isC—R⁸, R⁸ and R¹⁰ or two R⁸'s together may form a ring containing or notcontaining a hetero atom].
 2. The preventive or therapeutic medicine fordiabetes according to claim 1, wherein A is C-G {wherein G is CN, NO₂,CO₂R⁴ (wherein R⁴ is a hydrogen atom, an alkyl group which may besubstituted, an alkenyl group which may be substituted, an alkynyl groupwhich may be substituted, a cycloalkyl group which may be substituted, acycloalkenyl group which may be substituted, an aryl group which may besubstituted or a heterocyclic group which may be substituted), CHO,SO₂NR^(a)R^(b) (wherein each of R^(a) and R^(b) which are independent ofeach other, is a hydrogen atom, a hydroxyl group, an alkoxy group, analkyl group which may be substituted, an alkenyl group which may besubstituted, an alkynyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted, an aryl group which may be substituted or a heterocyclicgroup which may be substituted, or R^(a) and R^(b) together form a ring)or CONR^(a)R^(b) (wherein R^(a) and R^(b) are as defined above)}; eachof Y and Z which are independent of each other, is a nitrogen atom orC—R⁸ {wherein R⁸ is a hydrogen atom, a halogen atom, an alkyl groupwhich may be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted, a heterocyclic group which may besubstituted, a —B²—R⁹ group (wherein B² is CO, COO, O, OCO, OSO₂, S, SOor SO₂, and R⁹ is a hydrogen atom, an alkyl group which may besubstituted, an alkenyl group which may be substituted, an alkynyl groupwhich may be substituted, a cycloalkyl group which may be substituted, acycloalkenyl group which may be substituted, an aryl group which may besubstituted or a heterocyclic group which may be substituted), an aminogroup which may be substituted, a cyano group or a nitro group},provided that when Y and Z are simultaneously C—R⁸, the two R⁸'s may bethe same or different; and X is a nitrogen atom or C—R¹⁰ {wherein R¹⁰ isa hydrogen atom, a halogen atom, an alkyl group which may besubstituted, an alkenyl group which may be substituted, an alkynyl groupwhich may be substituted, a cycloalkyl group which may be substituted, acycloalkenyl group which may be substituted, a —B²—R⁹ group (wherein B²and R⁹ are as defined above), an amino group which may be substituted, acyano group or a nitro group}.
 3. The preventive or therapeutic medicinefor diabetes according to claim 1, wherein each of R¹ and R² which areindependent of each other, is a halogen atom, an alkyl group which maybe substituted, an alkenyl group which may be substituted, an alkynylgroup which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted, a heterocyclic group which may besubstituted, a —B^(1′)—R⁵ group (wherein B^(1′) is O or S, and R⁵ is ahydrogen atom, an alkyl group which may be substituted, an alkenyl groupwhich may be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted or aheterocyclic group which may be substituted), an amino group which maybe substituted or —N═CR⁶R⁷ (wherein each of R⁶ and R⁷ which areindependent of each other, is a hydrogen atom, an alkyl group which maybe substituted, an alkenyl group which may be substituted, an alkynylgroup which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted or a heterocyclic group which may besubstituted); and each of Y and Z which are independent of each other,is a nitrogen atom or C—R⁸ {wherein R⁸ is a hydrogen atom, a halogenatom, an alkyl group which may be substituted, an alkenyl group whichmay be substituted, an alkynyl group which may be substituted, acycloalkyl group which may be substituted, a cycloalkenyl group whichmay be substituted, an aryl group which may be substituted, aheterocyclic group which may be substituted, a —B^(2′)—R⁹ group (B isCO, COO, O, OCO or S, and R⁹ is a hydrogen atom, an alkyl group whichmay be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted or a heterocyclic group which may besubstituted), an amino group which may be substituted, a cyano group ora nitro group}.
 4. A stimulator of glucose uptake in skeletal musclecells, which contains the compound or its salt as defined in claim 1 asan active ingredient.
 5. A hypoglycemic agent which contains thecompound or its salt as defined in claim 1 as an active ingredient.
 6. Apreventive or therapeutic medicine for impaired glucose tolerance, whichcontains the compound or its salt as defined in claim 1 as an activeingredient.
 7. A preventive or therapeutic medicine for diabeticcomplications, which contains the compound or its salt as defined inclaim 1 as an active ingredient.
 8. The preventive or therapeuticmedicine for diabetic complications according to claim 7, wherein thediabetic complication is at least one member selected from the groupconsisting of hyperlipidemia, vascular diseases, retinopathy,nephropathy, neuropathy and hypertension.
 9. A preventive or therapeuticmedicine for obesity, which contains the compound or its salt as definedin claim 1 as an active ingredient.
 10. A fused-heterocyclic compound ofthe formula (I′) or its salt:

[wherein G is CN, NO₂, CO₂R⁴ (wherein R⁴ is a hydrogen atom, an alkylgroup which may be substituted, an alkenyl group which may besubstituted, an alkynyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted, an aryl group which may be substituted or a heterocyclicgroup which may be substituted), CHO, SO₂NR^(a)R^(b) (wherein each ofR^(a) and R^(b) which are independent of each other, is a hydrogen atom,a hydroxyl group, an alkoxy group, an alkyl group which may besubstituted, an alkenyl group which may be substituted, an alkynyl groupwhich may be substituted, a cycloalkyl group which may be substituted, acycloalkenyl group which may be substituted, an aryl group which may besubstituted or a heterocyclic group which may be substituted, or R^(a)and Rb together form a ring) or CONR^(a)R^(b) (wherein R^(a) and R^(b)are as defined above); R¹ is a halogen atom, a —O—R⁵ group (wherein R⁵is a hydrogen atom, an alkyl group which may be substituted, an alkenylgroup which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substitutedor a heterocyclic group which may be substituted) or a —S—R⁵ group(wherein R5 is as defined above); R² is a halogen atom, a —O—R⁵ group(wherein R⁵ is as defined above) or an amino group which may besubstituted; and each of R⁸ and R¹⁰ which are independent of each other,is a hydrogen atom, a halogen atom or an alkyl group].
 11. The compoundor its salt according to claim 10, wherein R² is an amino group whichmay be substituted.
 12. The compound or its salt according to claim 10,wherein R² is an amino group which may be substituted, and each of R⁸and R¹⁰ is a hydrogen atom.
 13. The compound or its salt according toclaim 12, wherein the amino group which may be substituted representedby R² is a —NR^(c)R^(d) group (wherein each of R^(c) and R^(d) which areindependent of each other, is a hydrogen atom, a —O—R⁵ group (wherein R⁵is a hydrogen atom, an alkyl group which may be substituted, an alkenylgroup which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substitutedor a heterocyclic group which may be substituted), an alkyl group whichmay be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted, an arylgroup which may be substituted or a heterocyclic group which may besubstituted, or R^(c) and R^(d) together form a ring).
 14. The compoundor its salt according to claim 10, wherein G is CN, CO₂R⁴ (wherein R⁴ isa hydrogen atom, an alkyl group which may be substituted, an alkenylgroup which may be substituted, an alkynyl group which may besubstituted, a cycloalkyl group which may be substituted, a cycloalkenylgroup which may be substituted, an aryl group which may be substitutedor a heterocyclic group which may be substituted), CHO, SO₂NR^(a)R^(b)(wherein each of R^(a) and R^(b) which are independent of each other, isa hydrogen atom, a hydroxyl group, an alkoxy group, an alkyl group whichmay be substituted, an alkenyl group which may be substituted, analkynyl group which may be substituted, a cycloalkyl group which may besubstituted, a cycloalkenyl group which may be substituted or aheterocyclic group which may be substituted, or R^(a) and Rb togetherform a ring) or CONR^(a) R^(b) (wherein each of R^(a′) and R^(b′) whichare independent of each other, is a hydroxyl group, an alkoxy group, analkyl group which may be substituted, an alkenyl group which may besubstituted, an alkynyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted, an aryl group which may be substituted or a heterocyclicgroup which may be substituted, or R^(a′) and R^(b′) together may form aring).
 15. A pharmaceutical composition which contains the compound orits salt as defined in claim 10 as an active ingredient.
 16. A methodfor producing a fused-heterocyclic compound of the formula (I′-1) or itssalt:

[wherein R¹, R⁸, R¹⁰ and G are as defined in claim 10], which comprisesreacting a compound of the formula (VII):

[wherein R¹ and G are as defined above; D is an alkoxycarbonyl group; Lis a halogen atom, a —OR⁵ group, a —SR⁵ group or a dialkylamino group(wherein R⁵ is as defined in claim 10)] with a compound of the formula(VIII):

[wherein R⁸ and R¹⁰ are as defined above].
 17. A method for producing afused-heterocyclic compound of the formula (I′-2) or its salt:

[wherein R¹, R⁸ and R¹⁰ are as defined in claim 10, G′ is CN, NO₂,SO₂NR^(a)R^(b) (wherein R^(a) and R^(b) are as defined in claim 10) orCONR^(a)R^(b) (wherein R^(a) and R^(b) are as defined above)], whichcomprises reacting a compound of the formula (VII′):

[wherein R¹ and G′ are as defined above, and L is a halogen atom, a —OR⁵group, a —SR⁵ group or a dialkylamino group (wherein R⁵ is as definedabove)] with a compound of the formula (VIII):

[wherein R⁸ and R¹⁰ are as defined above].
 18. A method for producing afused-heterocyclic compound of the formula (I′-3) or its salt:

[wherein R¹, R⁸, R¹⁰ and G are as defined in claim 10, and Hal is ahalogen atom], which comprises reacting the compound of the formula(I′-1) produced by the method as defined in claim 16, with ahalogenating agent.
 19. A method for producing a fused-heterocycliccompound of the formula (I′-4) or its salt:

[wherein R¹, R⁸, R¹⁰ and G are as defined in claim 10; and R5 is analkyl group which may be substituted, an alkenyl group which may besubstituted, an alkynyl group which may be substituted, a cycloalkylgroup which may be substituted, a cycloalkenyl group which may besubstituted, an aryl group which may be substituted or a heterocyclicgroup which may be substituted], which comprises reacting the compoundof the formula (I′-1) produced by the method as defined in claim 16,with a compound of the formula (IX): R^(5′)—L′ [wherein R^(5,) is asdefined above; and L′ is a halogen atom, a methanesulfonyloxy group or apara-toluenesulfonyloxy group].
 20. A method for producing afused-heterocyclic compound of the formula (I′-5) or its salt:

[wherein R¹, R⁸, R¹⁰ and G are as defined in claim 10; and Q is asubstituted amino group], which comprises (1) reacting the compound ofthe formula (I′-3) produced by the method as defined in claim 18 with acompound of the formula (IV-1): H-Q [wherein Q is as defined above], or(2) reacting the compound of the formula (I′-4) produced by the methodas defined in claim 19 with the compound of the formula (IV-1).
 21. Amethod for producing a fused-heterocyclic compound of the formula(I′-5′) or its salt:

[wherein R¹, R⁸ and R¹⁰ are as defined in claim 10; G′ is CN, NO₂,SO₂NR^(a)R^(b) (wherein R^(a) and R^(b) are as defined in claim 10) orCONR^(a)R^(b) (wherein R^(a) and R^(b) are as defined above); and Q is asubstituted amino group], which comprises reacting the compound of theformula (I′-2) produced by the method as defined in claim 17 with acompound of the formula (IV-2): L′-J [wherein J is a secondarysubstituent of the substituted amino group represented by Q; and L′ is ahalogen atom, a methanesulfonyloxy group or a para-toluenesulfonyloxygroup.